It is estimated that over 500,000 Americans suffer with orthostatic intolerance. Despite the magnitude of the number, this condition is still poorly understood and treated. In the past decade, evidence has accumulated demonstrating that the vestibular system contributes to postural blood pressure regulation. However, despite this knowledge, no intervention has been developed to activate the vestibular system and to improve orthostatic intolerance. Our long-term goal of this project is to further our understanding of how activation of the vestibular system participates in orthostasis in humans. The specific objectives of this R21 proposal are to: 1) examine the effect of ultrasonic bone stimulation of the mastoid (UBS) on muscle sympathetic nerve activity (MSNA) and vascular resistance, and 2) determine if UBS improves orthostatic tolerance in humans. The central hypotheses are that UBS augments MSNA and improves orthostatic intolerance in humans. We formulated these hypotheses, in part, based upon our strong preliminary data. As presented in the Preliminary Studies, we found that UBS increases MSNA and improves orthostatic tolerance in humans who have diminished capacity. The rationale for the proposed research is that once we know that UBS can increase MSNA and improve orthostatic intolerance, alternative treatments can be developed to assist patients who suffer from this disorder. We will pursue our objectives via two specific aims. Aim 1: To determine MSNA and vascular responses to UBS. Our working hypothesis for this aim is that UBS increases MSNA and vascular resistance to the leg and kidney in humans. This finding will be novel because no previous studies have used UBS to activate MSNA in humans. Aim 2: To determine if UBS improves orthostatic tolerance during head-up tilt. Our working hypothesis for this aim is that UBS improves orthostatic tolerance during head-up tilt. We will test this hypothesis by measuring the duration of head-up tilt with and without UBS in subjects that are afflicted by orthostatic intolerance. The findings will be novel because it will be the first time that UBS has been demonstrated to improve orthostatic intolerance in humans. Additionally, we will test a cohort of older subjects (>55 yr). Older individuals are more prone to orthostatic intolerance than younger subjects. In these studies, we will examine the prediction that UBS augments MSNA and improves orthostatic tolerance in humans. The proposed work is innovative because 1) it uses a new external device (i.e., UBS) to stimulate MSNA and 2) uses UBS to improve orthostatic intolerance in humans. At the completion of this project, it is our expectation that this work will have important implications i understanding the cause and the development of possible new treatment of orthostatic intolerance in otherwise healthy subjects. PUBLIC HEALTH RELEVANCE: The current project will contribute to our understanding the vestibular contributions to postural-mediated sympathetic activation and its relation to orthostati intolerance or hypotension in humans. Orthostatic hypotension is a risk factor for increased mortality in humans.